One of the most exciting advances in the last decade has been the development of therapies to preserve hearing under conditions of stress that can otherwise cause hair cell loss. Current therapies, however, focus on preservation of sensory cells and recent results (Kujawa and Liberman, 2006, 2009) indicate that the connections between inner hair cells (IHC) and auditory nerve (AN) may also be at risk for permanent loss. Our proposed studies examine loss of IHC-AN connections during two stresses chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing, then test the efficacy of anti-oxidant (AO) therapy for protection / recovery and finally determine if adding anti- excitotoxicity therapy to the AO therapy will improve protection / recovery of IHC-AN connections and hearing. Aim 1-Test the hypothesis that a moderate noise causing permanent loss of many hair cells will also produce a permanent loss of many IHC-AN connections on remaining IHCs and later loss of auditory neurons (SGN). Aim 2- Test the hypothesis (2a) that AO treatments that effectively reduce noise-induced hair cell loss will be less effective in reducing the loss of IHC-AN connections and (2b) that adding a specific anti-excitotoxicity therapy will improve preservation of IHC-AN connections, long term survival of SGN and hearing. Aim 3 - Test the hypothesis that trauma from insertion of a prostheses into a hearing ear will induce loss of IHC-AN connections, including in regions where hair cells are not lost. Aim 4 - Test the hypothesis (4a) that adding AO treatment will be more effective in preserving hair cells than IHC-AN connections from the trauma of prostheses insertion and (4b) addition of specific anti-excitotoxicity therapy to the AO therapy will improve the preservation of IHC-AN connections. Aim 5 - Test the hypothesis that reducing loss of IHC-AN connections and SGN will improve acoustic hearing and spatial and temporal acuity of psychophysical responses to cochlear implant stimulation. Results of the proposed studies will redefine and broaden treatment targets for preserving hearing with high impact not only toward treating the two conditions being tested, noise-induced hearing loss and implantation of cochlear prostheses into ears with remaining hearing, but with high relevance towards best treatment practices for other inner ear pathologies ranging from ototoxicity to vestibular disorders. If successful, a new treatment paradigm can be directly translated to clinical trials and benefit millions of individuals worldwide. PUBLIC HEALTH RELEVANCE: Our proposed studies are to develop and test better treatments to preserve hearing during two traumatic stresses to the ear, chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing.